Tyrosine protein kinases (TPKs) are able to catalyse the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. TPK are a subgroup of the larger protein kinase class of enzymes. The enzymes' ability to phosphorylate is an important mechanism in signal transduction for the regulation of cellular activity. Cellular proliferation in thought to rely (at least to some extent) on TKRs. Mutations can cause some TPKs to become constitutively active, and this aberrant activity has been thought to contribute to initiation or progression of proliferative disorders such as cancer. Accordingly, in relation to the treatment of diseases and conditions characterised by the proliferation of cells the TPK subgroup of enzymes represents an attractive target.
A family of proto-oncogenic TPKs referred to herein as SFKs (Src family kinases) have provided researchers with a better understanding of the mechanism of cancer as a disease state where normally healthy cellular signalling is disrupted. SFKs have been observed to play a critical role in cell adhesion, invasion, proliferation, survival and angiogenesis during tumour development.
SFKs comprise nine family members that share similar structure and function. The nine members are c-Src, Yrk, Yes, Fyn, Fgr, Lyn, Lck, Hck, and Blk. The overexpression or high activation of these SFKs has been observed in many tumours.
SFKs can interact with tyrosine kinase receptors, such as the EGFR and the VEGF receptor. SFKs are thought to affect cell proliferation through the Ras/ERK/MAPK pathway and may regulate gene expression via transcription factors such as STAT molecules. SFKs like some other TPKs can also affect cell adhesion and migration. The SFKs are thought to act via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130CAS and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs have also been shown to regulate angiogenesis via gene expression of angiogenic growth factors, such as VEGF, interleukin 8, and fibroblast growth factor.
Due to this recognition and better understanding as to role being played by TPKs in general and SFKs in particular, small-molecule SFK inhibitors are being developed for the treatment of hyperproliferative disorders such as cancer. At this stage however of a number of promising SFK inhibitors (e.g., Bosutinib, AZ0530, and Desatinib as shown below) only Desatinib is approved whereas the others are presently still undergoing clinical trials and as such there is no guarantee that any further acceptable SFK inhibitor (based on the currently recognised compounds) will reach the market.
